1. Field of the Invention
The invention relates to reactive chlorine compounds such as dichloric acids, the intermediate product peroxochloric acid as well as peroxochlorous acid and their individual derivatives, anions, and/or salts. It further relates to processes for manufacturing these compounds and their use in the pharmaceutical field, here in particular, in medical treatment as drugs and disinfectants, in the fields of cosmetics and medicinal care as histocompatible deodorants, in the field of foodstuff treatment and technology, in particular in the preservation of foods and beverages, as a bleaching agent and for drinking water disinfection, in the antimicrobial treatment of plants and fruits in agriculture, and as an oxidizing agent in technical chemistry and for cleaning waste gas.
2. Related Technology
Oxidizing agents have a very wide range of applications in technical chemistry, in hygiene and in food preservation, in cosmetics and also in pharmaceutical uses.
According to Polly Matzinger (Polly Matzinger: “Tolerance, Danger, and the Extended Family” in Annu. Rev. Immunol. 1994, 12) cells dying due to violence, i.e. through massive radiation effects, toxic substances, parasitic, bacterial or viral infective agents, lytic, non-apoptotic effects, emit danger signals. These must persist so that the body's own defences, which as well as the actual antigen signal require a non-specific co-stimulation from antigen-presenting cells (e.g. macrophages), can have an optimum clinical effect.
During a violent, non-apoptotic cell death, phagocytes (so-called micro and macrophages) are responsible for cellular debris disposal. In this debris disposal process oxidatively effective oxygen metabolites are released. Hydrogen peroxide (H2O2) is the most well-known of these substances. In-vitro-trials show that, in the micromolar range, H2O2 can lead to an immune modulation of lymphocytes via the activation of the transcription factor HF-kappa B (R. Schreck et al., The EMBO Journal 10(8), 2247-58 (1991); M. Los et al., Eur. J. Immunol. 25, 159-65 (1995). The working group of Avraham Novogrodsky was the first to demonstrate in vitro that certain oxidizing agents (Bowers W. E.: “Stimulation of Lymphocytes with Periodate or Neuraminidase plus Galactose Oxidase—NAGO” p. 105-109, Review in Immunochemical Techniques Part K Methods in Enzymology Vol. 150, 1987), among other effects, also increase the H2O2 formed in the body itself co-mitogenically by lymphocyte proliferation due to antigen stimulation, if macrophages are simultaneously present in the lymphocyte culture (Stenzel K. H., Rubin A. L., Novogrodsky A.: “Mitogenic and Comitogenic Properties of Hemin.” J. Immunol. 127, 6: 2469-2473 et ibid. cit. ref.). An immune response will be incomplete or not even take place at all if the oxidatively effective oxygen metabolites are not formed in sufficient quantities in the body. Thus a tolerance or pathological anergy results. If the metabolites are produced excessively or for a disproportionately long period, then chronic inflammation and tissue scars will form.
As a result of these findings, one can assume that oxidatively effective oxygen compounds will have a therapeutic effect, particularly in such clinical situations where their endogenous formation is insufficient or deteriorates before the body injuries have completely healed and the infective agents have been totally removed. A treatment success is expected especially in those cases where the cells are indeed affected by the infection but not destroyed and therefore do not emit “danger signals”. Exemplary here are infections with leprosy and tuberculosis bacilli as well as infections caused by herpes and AIDS (HIV) viruses.
A report was published as early as 1906 on the successful clinical use of potassium bichromate in the healing of ichorous chronic wounds (Fenwick, J.: “The Treatment of Cancer by the Use of Potassium Bichromate”, British Medical Journal, Mar. 6, 1909, 589-591).
Further numerous publications, which have appeared in the meantime, show that hydrogen peroxide formed physiologically within the body—as well as the in vivo even more short-lived peroxonitrite which can also form from the equally physiological nitroxide and hydrogen peroxide—also demonstrates wound healing effects, whereby a positive immunomodulation plays an essential role. For example, the EPA-0390829 describes a method for increasing the syngenic intradermal cell proliferation through human growth factors using hydrogen peroxide injections. Such a comitogenic increase in the growth factor effects of interleukin-2 was also described for periodate in 1987 (Wang J. et al., The American Journal of Medicine 1987, 83: 1016-1023).
It is known that (co)mitogenic oxidants have intolerable side effects, such as e.g. for bichromate:—the now recognized carcinogenic effect of chromium oxide: For periodate:—iodine hypersensitivity and toxic effects. Therefore, their clinical use has to take place laboriously as an “adoptive transfer”, i.e. the blood cells are taken out, treated in vitro and then returned in vivo—as described in the previously quoted study by J. Wang et al. 1987. For NAGO side effects are:—the foreign protein sensitization: For H2O2:—the formation of toxic oxygen radicals. Here too, there are also technical problems concerning their use as drugs, e.g. for H2O2:—short storage life in diluted aqueous solution; the catalase lability with massive oxygen gas release. For oxidized ubichinon derivatives problems are:—pharmaceutical manufacturing problems and limited bioavailability.
Therefore, it was not possible up to now to transfer the experimentally demonstrated immunopharmacological action of (co)mitogenic oxidants in clinical practice into tissue regeneration/wound healing, infection resistance and the strengthening of the immune response. In clinical practice, as well as a local application, a systemic treatment, usually in the form of an intravenous administration, is also desirable.
Theo Gilbert Hinze (US 2003/0133878 A1, “American Composition for the treatment of legionella pneumophila and a method for such treatment”) processed aqueous solutions of NaCl or KCl2 (presumably the latter chemical formula here is a printing error) with electrochemical oxidation at pH 6.5-7.5. It was conjectured that, as well as other ions, only the Cl2O62− ion could be present which at that time had been described only in the preceding invention. This dimer contains the chlorine atoms in the +3 and +5 valence states.
The patent literature contains descriptions of a few further chlorine-oxygen preparations which are particularly used in such technical fields where they serve as oxidants not only in industrial technology as bleaching agents and deodorants, but also where they are recommended for paramedical applications such as in cosmetics for skin and hair care, for household cleaning, in the sanitary sector for hygiene and/or as disinfectants for surfaces (U.S. Pat. Nos. 2,701,781; 3,123,521) and/or wounds (U.S. Pat. No. 4,084,747; EP-A-0 744 895), as preservation agents for cheese (U.S. Pat. No. 3,147,124) and for the conditioning of drinking and bathing water (U.S. Pat. No. 4,296,103; DE-A-44 05 800, DE-A-19 518 464; WO 96/33947; WO 97/06098). The U.S. Pat. No. 4,296,103, EP-A-0 136 309, U.S. Pat. No. 4,507,285 and EP-A-0255145 describe the medical application of chlorine-oxygen preparations.
WO 00/48940 contains a description of the preparation of a chlorohydroperoxide with the formula HOOClO2 where the chlorine has valence of 5. This hydroperoxide behaves as an acid which supplies the anion O2ClOO− in an aqueous environment. Therefore, it was called peroxochloric acid and its anion is called peroxochlorate. It is reported that the combination of two peroxochlorate ions, under separation of an oxygen molecule, can lead to derivatives of peroxochlorate with one peroxo group and two chlorine atoms with different valences. This ion is allocated the empirical formula (Cl2O6)2−.
It is disclosed that it would be possible to manufacture stable peroxochloric acid and stable salts or anions thereof in solution. For example, these compounds are obtained in aqueous solution by the reaction of chlorine dioxide with hydrogen peroxide if the work is carried out at pH values which are equal to, or greater than, the pKs value of peroxochloric acid (HOOClO2). pH values of 6.5 and more are preferable, and the pH range of 10-12 is especially preferable.
Thus, in WO 00/48940 peroxochloric acid or its salts, peroxochloric acid and its salts or anions in aqueous solution, oligomeric derivatives of the peroxochlorate with mixed-valent chlorine atoms and their salts or anions in aqueous solution as well as the carbon dioxide adduct as an acid, an anion in solution or as a salt are disclosed.
In the meantime, it has been proved that an isolation of a crystalline metallic salt of peroxochlorate, according to the specifications given in WO 00/48940, is unsuccessful.
Due to the low concentrations of peroxochlorate in the preparations manufactured according to the specifications of WO 00/48940, it is only possible to prepare the deoxo dimers to a limited degree.
Svensson and Nelander published the preparation of HOOClO2 at low temperatures of 17K (−256, 15° C.) in J. Phys. Chem. A 1999, 103, 4432-4437.
Therefore, all the published chlorine-oxygen preparations do not fulfil the requirement criteria of modern drug approval. These state that the pharmacodynamics of the preparation must be allocatable to a chemically defined compound as the so-called active substance which is to be standardized as the pharmaceutical product. This is also necessary in order to guarantee homogeneous drug quality.
The intrinsically good chlorine-oxygen compounds of WO 00/48940, and in particular the deoxo dimer defined there, can, up to now, only be manufactured to a limited degree. Therefore, a commercial exploitation appears to be impossible.